γ-Secretase is a complex protein (a member of the aspartate protease family) comprising presenilin, nicastrin, Aph-1 (“anterior pharynx defective 1”) and Pen-2 (“presenilin enhancer 2”) as basic components. Presenilin is the catalytic domain; the presenilin gene has been identified as a causative gene for familial Alzheimer's disease (AD). γ-Secretase acts on single-pass transmembrane proteins as its substrates. Representative substrates of γ-secretase are amyloid precursor protein (APP) and Notch. When cleaved by β-secretase at the β-site and by γ-secretase at the γ-site, APP produces amyloid βprotein (Aβ). The thus-produced Aβ is classified into peptides with different lengths depending on the cleavage site in the amino acid sequence (C-terminal side). Of these peptides, Aβ42 which is strongly hydrophobic and ready to aggregate (ready to take the β-sheet structure) exhibits neurotoxicity. It has been considered that this phenomenon may be the major cause of Alzheimer's disease. Recently, however, a report has been made that presenilin 1 (PS1) and presenilin 2 (PS2) double-knockout mice capable of producing no Aβ show AD-like phenotypes such as decrease of synapses and neuronal death; this suggests the existence of a pathogenic mechanism of AD that is independent from APP (see Saura C A, Choi S Y, Beglopoulos V, Malkani S, Zhang D, Shankaranarayana Rao B S, Chattarji S, Kelleher R J 3rd, Kandel E R, Duff K, Kirkwood A, and Shen J., “Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration,” Neuron 42(1):23-36 (Apr. 8, 2004)).
On the other hand, Eph receptor A4 (EphA4) is a member of the receptor tyrosine kinase family, and is a molecule regulating the morphogenesis of post-synapses. It is known that EphA4 knockout or expression of EphA4 dominant-negative mutants causes a decrease in the number of dendritic spines (small, thorn-like protrusions found on dendrites) and makes the spine shape slender (see Murai K K, Nguyen L N, Irie F, Yamaguchi Y, Pasquale E B, “Control of hippocampal dendritic spine morphology through ephrin-A3/EphA4 signaling,” Nat Neurosci.; 6(2):153-60 (February 2003)). It is generally proposed that the processes of memory and learning are reflected by the number of and the morphology of the spines.
However, it has never been reported to date that EphA4 is a substrate for γ-secretase.